Alzheimer's Disease (AD) is a degenerative disorder of the human central nervous system characterized by progressive memory impairment and cognitive and intellectual decline during mid to late adult life (Katzman, N Eng J Med 1986;314:964-973). The disease is accompanied by a constellation of neuropathologic features principal amongst which are the presence of extracellular amyloid or senile plaques, and neurofibrillary tangles in neurons. The etiology of this disease is complex, although in some families it appears to be inherited as an autosomal dominant trait. Genetic studies have identified three genes associated with the development of AD, namely: (1) β-amyloid precursor protein (βAPP) (Chartier-Harlin et al., Nature 1991;353:844-846; Goate et al., Nature 1991;349:704-706; Murrell et al., Science 1991:254:97-99; Karlinsky et al., Neurology 1992;42:1445-1453; Mullan et al., Nature Genetics 1992;1:345-347); (2) presenilin-1 (PS 1) (Sherrington et al., Nature 1995;375:754-760); and (3) presenilin-2 (PS2) (Rogaev et al., Nature 1995;376:775-778; Levy-Lehad et al., Science 1995; 269:970-973).
Abnormal processing of βAPP with overproduction of amyloid-β is also a feature of other CNS diseases, including inherited and sporadic forms of amyloid angiopathy, which presents with intracerebral bleeding (Levy et al., Science 1990;248:1124-1126). Thus, abnormalities of presenilin proteins and PS-interacting proteins may affect these diseases as well.
The presenilin genes (PS1-PS1 and PS2-PS2) encode homologous polytopic transmembrane proteins that are expressed at low levels in intracellular membranes including the nuclear envelope, the endoplasmic reticulum, the Golgi apparatus and some as yet uncharacterized intracytoplasmic vesicles in many different cell types including neuronal and non-neuronal cells (Sherrington et al., supra; Rogaev et al., supra; Levy-Lahad et al., supra; Doan et al., Neuron 1996;17:1023-1030; Walter et al., Molec. Medicine 1996;2:673-691; De Strooper et al., J. Biol. Chem. 1997;272:3590-3598; Lehmann et al., J. Biol. Chem. 1997;272:12047-12051; Li et al., Cell 1997;90:917-927). Structural studies predict that the presenilins contain between six and eight transmembrane (TM) domains organized such that the N-terminus, the C-terminus, and a large hydrophilic loop following the sixth TM domain are located in the cytoplasm or nucleoplasm, while the hydrophilic loop between TM1 and TM2 is located within the lumen of membranous intracellular organelles (Doan et al., 1996; De Strooper et al., 1997; Lehmann et al., 1997).
Missense mutations in the PS1 and PS2 genes are associated with the inherited forms of early-onset AD (Sherrington et al., Nature 1995;375:754-760; Rogaev, et al., Nature 1995;376:775-778; Levy-Lahad et al, Science 1995;269:970-973). Several lines of evidence have also suggested roles in developmental, apoptotic signalling and in the regulation of proteolytic cleavage of the β-amyloid precursor protein (βAPP) (Levitan et al., Nature 1995;377:351-354; Wong et al., Nature 1997;387:288-292; Shen et al., Cell 1997;89:629-639; Wolozin et al., Science 1996;274:1710-1713; De Strooper et al., Nature 1998;391:387-390). Nevertheless, it remains unclear just how these putative functions are mediated, or how they relate to the abnormal metabolism of the βAPP associated with PS1 and PS2 mutations (Martin et al., NeuroReport 1995;7:217-220; Scheuner et al., Nature Med. 1996;2:864-870; Citron et al., Nature Med. 1997;3:67-72; Duff et al., Nature 1996;383:710-713; Borchelt et al., Neuron 1996;17:1005-1013).
PS1 and PS2 interact specifically with at least two members of the armadillo family of proteins; neuronal plakophilin-related armadillo protein (Paffenholtz et al., Differentiation 1997; 61: 293-304; Paffenholtz et al., Exp Cell Res 1999; 250: 452-464; Zhou et al., Neuroreport 1997; 8: 2085-2090) and β-catenin, that are expressed in both embryonic and post-natal tissues. Moreover, the domains of PS1 and PS2 that interact with these proteins have been identified. Mutations in PS1 and PS2 affect the translocation of β-catenin into the nucleus of both native cells and cells transfected with a mutant PS gene. These interactions and effects are described in detail in co-pending commonly assigned U.S. application Ser. No. 09/227,725, filed Jan. 8, 1999, the disclosure of which is incorporated herein by reference.
The identification and cloning of normal as well as mutant PS1 and PS2 genes and gene products are described in detail in co-pending commonly assigned U.S. application Ser. No. 08/431,048, filed Apr. 28, 1995; Ser. No. 08/496,841, filed Jun. 28, 1995; Ser. No. 08/509,359, filed Jul. 31, 1995; and Ser. No. 08/592,541, filed Jan. 26, 1996, the disclosures of which are incorporated herein by reference.
There is speculation that onset of AD may be associated with aberrant interactions between mutant presenilin proteins and normal forms of PS-interacting proteins, and these changes may increase or decrease interactions present with normal PS1, or cause interaction with a mutation-specific PS-interacting protein. Such aberrant interactions also may result from normal presenilins binding to mutant forms of the PS-interacting proteins. Therefore, mutations in the PS-interacting proteins may also be implicated in the development of AD.
While the identification of normal and mutant forms of PS proteins has greatly facilitated development of diagnostics and therapeutics, a need exists for new methods and reagents to more accurately and effectively diagnose and treat AD. In addition, further insights into PS proteins and their interaction with other components may lead to new diagnostic and treatment methods for other related CNS diseases.